Methamphetamine (MA) abuse is associated with significant consequences to social and personal health. Neuroglia activation / neuroimmune signaling is increasingly recognized as a novel therapeutic target for MA addiction. This notion is based on animal data suggesting involvement of altered brain glial functions and neuroinflammatory factors in this condition and findings that some drugs with neuroimmune properties reduce addiction relevant behaviors (e.g. drug-seeking in rodents). Although animal studies suggest some brain glial activation following MA exposure, the data remain scanty and contradictory in the human. There is need to establish whether the brain animal findings have any relevance to the human MA user. Following upon our development of [18F]-FEPPA, a non-invasive PET imaging probe which can assess glia activation via measurement of TSPO binding, our major specific aim and hypothesis is to establish by PET imaging whether brain glial activation is elevated in chronic MA users during early withdrawal. As a secondary aim, we will examine the relationship between glial activation ([18F]-FEPPA / TSPO PET binding), oxidative stress (glutathione [GSH] via MRS) and peripheral blood measures of immune markers and explore whether those might be related to behavior and neural impairment characteristic of MA withdrawal. MA users will participate in a PET imaging session with [18F]-FEPPA and an MRI/MRS session to provide structural information needed for PET data analysis as well as GSH levels (MRS) and functional connectivity (rsMRI). MA users will be scanned in early abstinence to maximize chance of seeing an effect and subjective assessments of craving, mood, withdrawal and cognitive state taken. Blood will be drawn for measurement of immune markers, permitting exploration of relationship between PET/MRI-MRS outcome measure and peripheral measures. Confirmation of our hypothesis conducted by a team having a track record in both postmortem and living brain assessment of glial status, can help guide clinical application of treatment approaches targeting the neurolglial cell and possibly neuroimmune response. Project will also provide the first simultaneous imaging investigation of microglia activation and oxidative stress in MA users. Further, assessment of the relationship between brain and peripheral (blood) markers in MA addiction is highly innovative, a first in this condition, and will address the unmet need for identification of simple, noninvasive and inexpensive biomarkers of CNS damage.